Protein Misfolding Disease: Overview of Liquid and Solid-State High Resolution NMR Studies

The failure of proteins to fold into their functional forms can occasionally lead to „protein misfolding“ or „protein conformational“ diseases. Many among themostcommon and debilitating of these diseases are associated with the formation of protein amyloid, an insoluble material that is deposited as fibrils or plaques in different tissues and organs of the body. Amyloid formation is known to be accelerated by a variety of cellular factors, including metal ions, such as copper and zinc, and interactions with other species, such as lipids and RNA. It is implicated in many medical conditions including Alzheimer’s disease and the transmissible prion disorders. It is becoming increasingly recognized that the switch from a normal to a diseased state of the cell in protein misfolding diseases is induced by a shift in the equilibrium between different conformational and aggregation states of a polypeptide chain that are present under normal conditions. The native state [N] of a protein can be investigated in great detail using X-ray crystallography and NMR-spectroscopy. Our understanding of states other then the native one, however, is only now emerging. Liquid and solid-state high-resolution NMR spectroscopy are the major structural techniques to determine structure and dynamics of the polypeptide chain under a variety of different conditions. They describe proteins in their native state [N], in unfolded states [U], in transient intermediates [I], and in their fibrillar and prefibrillar states (Figure 1).